Cancer is a major public health problem and a leading cause of mortality, claiming more than half million lives every year in the US. While major progresses have been made in developing targeted anticancer therapeutics, many cancers such as lung cancers have no effective treatments. Unfortunately, many ideal oncogenic targets including transcription factors for these cancers are considered undruggable and simply avoided for discovery of targeted therapeutics. STAT3, a transcription factor in the Janus kinase (JAK)/STAT signaling pathway, is constitutively activated in most human cancers including lung and breast cancers and has been shown to drive tumorigenesis. Thus, STAT3 is a sought-after target for discovery of anticancer drugs. Indeed, targeting the SH2 domain of STAT3 for drug discovery has been attempted. However, the clinical efficacy of these inhibitors is limited and some are poorly tolerated in humans. On the other hand, targeting the DBS of STAT3 has not been in the main stream of research due to the taboo that the DNA-binding site (DBS) is undruggable. Using an improved in-silico screening approach, a STAT3-selective small molecule inhibitor (inS3-54) targeting the DBS of STAT3 was recently identified, which effectively inhibits cancer cell proliferation, migration, and invasion. These findings suggest tha the DBS of STAT3 may be druggable, challenging the prevailing dogma of DBS as an undruggable site and may promise a potential therapeutics for the difficult to treat human cancers. The long-term objective of QRKanswer, LLC, an Indiana-based small business, is to investigate inhibitors targeting the DBS of STAT3 for potential drug development. In this Phase I STTR application, QRKanswer and its research partners at Indiana University School of Medicine plan to investigate the active analogues of inS3-54 and newly synthesized new composition of matters to identify lead inhibitors for potential anticancer drug development. To this end, two aims will be accomplished to (1) evaluate the active inS3- 54 analogues and new composition of matters using in-vitro cell-based assays and (2) evaluate the lead analogues for preclinical pharmacokinetics, toxicity, and efficacy. At the conclusion of this study, QRKanswer will have a lead inhibitor targeting the DBS of STAT3 with preclinical data for Phase II study, in which QRKanswer will further investigate the lead compound for filing IND and potentially testing safety in phase I clinical trial of solid tumors such as breast and lung cancers with estimated 234,190 and 221,200 new cases in 2015, respectively. The successful outcome will help QRKanswer gain entry into this market.